Clinical and Pharmacological Effects of Apixaban Dose Adjustment in the ARISTOTLE Trial
Key result
Apixaban 2.5 mg BID maintains efficacy and safety versus warfarin despite lower drug exposure.
- n=18,073
Why the study?
The study was conducted to describe the effects of apixaban dose adjustment (2.5 mg twice daily vs warfarin) on clinical and pharmacological outcomes in patients meeting dose-adjustment criteria.
Does apixaban 2.5 mg twice daily provide consistent clinical and pharmacological effects compared to warfarin in atrial fibrillation patients with ≥2 dose-adjustment criteria?
Key Points
- This study aims to evaluate the clinical and pharmacological outcomes of apixaban dose adjustment in patients with atrial fibrillation.
- Patients with ≥2 dose-adjustment criteria (n=18,073) were randomized to apixaban 2.5 mg or warfarin.
- The effects on pharmacokinetics, D-dimer, and prothrombin fragment 1+2 were analyzed against standard dose apixaban (5 mg).
- Outcomes for stroke, major bleeding, and all-cause death were compared between dose groups.
- Patients on apixaban 2.5 mg showed lower drug exposure (AUC 2,720 ng/ml vs. 3,599 ng/ml; p<0.0001).
- Those with ≥2 adjustment criteria had a higher risk of stroke/systemic embolism, major bleeding, and all-cause death compared to standard dose.
- The efficacy and safety profiles of apixaban 2.5 mg were consistent with warfarin in the same population.
Study Design
Type
RCT (n=18,073)
Structured PICO
Does apixaban 2.5 mg twice daily provide consistent clinical and pharmacological effects compared to warfarin in atrial fibrillation patients with ≥2 dose-adjustment criteria?
P
Population
18,073 patients with atrial fibrillation, including 751 meeting ≥2 dose-adjustment criteria, evaluated for the pharmacological and clinical effects of apixaban 2.5 mg twice daily versus warfarin.
I
Intervention
Apixaban 2.5 mg twice daily (for patients with ≥2 dose-adjustment criteria) or 5 mg twice daily (standard dose)
C
Comparator
Warfarin
O
Outcome
Population pharmacokinetics, D-dimer, prothrombin fragment 1 + 2 (PF1+2), stroke or systemic embolism, major bleeding, and all-cause deathhard clinical
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Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Even in people who do meet the dose-reduction criteria, [the 2.5-mg dose] results in lower concentrations of apixaban, and based on what we know about apixaban's clearance, those concentrations can only be lower in people who don't meet the dose-reduction criteria.”
“Those are very important reassuring data on efficacy and safety.”
“The data reported by Zeitouni et al will be welcomed by clinicians, but an important knowledge gap remains concerning t”
Implication
Apixaban 2.5 mg twice daily in patients with atrial fibrillation and ≥2 dose-adjustment criteria provides consistent efficacy and safety compared to warfarin as the standard 5 mg dose.
Abstract
BACKGROUND In the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, patients with atrial fibrillation and ≥2 dose-adjustment criteria (age ≥80 years, weight ≤60 kg, or creatinine ≥1.5 mg/dl [133 μmol/l]) were randomized to receive apixaban 2.5 mg twice daily or warfarin. OBJECTIVES The purpose of this study was to describe the effects of apixaban dose adjustment on clinical and pharmacological outcomes. METHODS Patients receiving the correct dose of study drug were included (n = 18,073). The effect of apixaban 2.5 mg twice daily versus warfarin on population pharmacokinetics, D-dimer, prothrombin fragment 1 + 2 (PF1+2), and clinical outcomes was compared with the standard dose (5 mg twice daily). RESULTS Patients receiving apixaban 2.5 mg twice daily exhibited lower apixaban exposure (median area under the concentration time curve at a steady state 2,720 ng/ml vs. 3,599 ng/ml; p < 0.0001) than those receiving the standard dose. In patients with ≥2 dose-adjustment criteria, reductions in D-dimers (p interaction = 0.20) and PF1+2 (p interaction = 0.55) were consistent with those observed in the standard-dose population. Patients with ≥2 dose-adjustment criteria (n = 751) were at higher risk for stroke/systemic embolism, major bleeding, and all-cause death than the standard-dose population (0 or 1 dose-adjustment criterion, n = 17,322). The effect of apixaban 2.5 mg twice daily versus warfarin in the ≥2 dose-adjustment criteria population was consistent with the standard dose in the reductions in stroke or systemic embolism (p interaction = 0.26), major bleeding (p interaction = 0.25), and death (p interaction = 0.72). CONCLUSIONS Apixaban drug concentrations were lower in patients receiving 2.5 mg twice daily compared with 5 mg twice daily. However, the effects of apixaban dose adjustment to 2.5 mg versus warfarin were consistent for coagulation biomarkers and clinical outcomes, providing reassuring data on efficacy and safety. (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation [ARISTOTLE]; NCT00412984).
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Cite This Study
Zeitouni et al. (2020) conducted an RCT in Atrial fibrillation (n=18,073). Apixaban vs. Warfarin and standard dose apixaban (5 mg twice daily) was evaluated on Stroke or systemic embolism, major bleeding, and all-cause death. Apixaban dose adjustment to 2.5 mg twice daily resulted in lower drug exposure (median AUC 2,720 vs 3,599 ng/ml; P<0.0001) but maintained consistent clinical efficacy and safety versus warfarin.